The present invention is directed to a method for performing automatic transfer of liquid samples between a plurality of receptacles. More specifically, it is directed to a system for filling, or transferring liquid samples between, a multiplicity of separate liquid receptacles, such as is required in initial filling and serial dilution of liquid samples in microtiter trays where each receptacle holds only about one tenth to ten milliliters of liquid. Such a serial dilution system basically involves mixing the sample with successively increasing proportions of a diluent in separate receptacles thereby to obtain a series of successively decreasing concentrations of the sample. The various sample concentrations can then be assayed to determine a particular property. For example, the sample might be a serum and the assay might be used to determine which concentration of the serum provides optimum results when reacted with a particular substance.
Initially, serial dilution of a sample was performed manually, wherein different proportions of the sample would be mixed with diluent contained in different respective test tubes, for example with the aid of a syringe or pipette. This procedure consumed a considerable amount of time when a number of different concentrations were required. Consequently, machines for automatically or semi-automatically performing serial dilutions were developed. One example of such a machine is disclosed in U.S. Pat. No. 3,188,181. The serial dilution machine disclosed in that patent includes a horizontally movable carriage that accommodates a rack of test tubes. A vertically movable syringe holder housing a plurality of off-the-shelf syringes respectively connected to pipettes is raised and lowered by means of a cam to bring the pipettes into the liquid volume in a row of test tubes within the rack. A cam operated pumping head oscillates the syringes to mix fluid in the pipettes with that in the test tubes. After mixing, fluid is withdrawn from the test tubes, the syringe holder is lifted, and the carriage is incremented to another row of test tubes to repeat the operation. When the serial dilution operation is complete, a first row of test tubes in the rack might contain undiluted concentrations of the sample, the second row of test tubes would contain a 50/50 concentration of the sample, the third row would be a 25/75 concentration, and so forth, depending on the amount of liquid transferred by the pipettes.
It is an object of the present invention to provide a novel system for automatically effecting transfer of liquid between receptacles without cross contamination or errors in the quantity of liquid so transferred and which is particularly useful in performing serial dilution of small liquid samples with substantially improved performance over that possible with the machine of the previously noted patent. More particularly, when handling certain types of solutions, it is desirable to prevent cross-contamination between various sample concentrations. Typically, this is done in the manual method by utilizing disposable tips on the pipettes that withdraw the liquid from one receptacle and mix it with diluent in another. After each mixing operation, the tip is removed from the pipette and replaced with a clean one. However, heretofore known serial dilution machines do not offer the ability to change tips between each cycle in the serial dilution process. Consequently, when prevention of cross-contamination is desired, the machine must effect a multi-step washing process for the pipettes, or provide a flushing process between each cycle in the process. The washing process substantially increases the time that is required to effect a serial dilution since a number of steps are added in each cycle of the process. The flushing procedure generates a considerable amount of waste liquid that must be disposed of.
Accordingly, it is a more particular object of the present invention to provide a novel automatic serial diluter arrangement that is capable of automatically changing disposable tips on pipettes in a quick and efficient manner in any desired cycle of the serial dilution process from initial fill of the liquid receptacles through any of a selectable plurality of addition or subtraction steps to transfer liquid between the receptacles.